The fertility processes which occur in females, especially in human females, are highly complex, and continuing efforts are being made in this area to more fully understand these processes so as to facilitate the development of improved techniques for predicting and treating fertility problems as well as for providing more effective and reliable birth control methods. A number of drugs have been employed to treat infertility. Clomiphene citrate is one such drug. However, in the fertility problem area, there still is an acute need for improved methods for studying, as opposed to treating, women who wish to conceive but are unable to do so. For example, a woman seeking a career outside the home may consider postponing childbearing until her thirties, and a prognosticator of fecundity would be of special value to her. It might guide her decisions regarding pregnancy attempts and contraception. It also would aid the physician in clinical decisions regarding infertility workup or therapy. Moreover, this need extends to women experiencing other difficulties such as menstrual cycle variations and other problems associated with the female child bearing organs. However, for the apparently healthy, regularly menstruating woman, age is presently the only widely accepted parameter of fertility potential. Demographic studies indicate that fertility peaks during the early twenties, decreases noticeably after 30 years of age and markedly after 35 years. However, because of individual variations, age by itself is an inaccurate parameter, and arbitrary limits based on age alone can influence treatment decisions in a number of patients.
In the birth control area, there is also an acute need for improved birth control methods which are not only effective in preventing conception but also have a reduced incidence of adverse physical side effects. There are a wide variety of birth control methods available, but these are often unacceptable due to the fact that they are unreliable (i.e., prevention of conception is not assured), or for medical reasons, or on religious grounds. One example of a birth control method which is unreliable is the so-called "rhythm" method, which is based on the fact that the woman is not fertile, i.e., ovulation has not occurred or is not about to occur, during a certain period in her menstrual cycle. The major disadvantage associated with this method is that, while the time period from when ovulation naturally occurs to the next succeeding menstrual period is essentially fixed in all women, the time period between the beginning of a menstrual period and the next ovulation can vary considerably depending of the particular woman concerned. It is during the time period between the beginning of a menstrual period and the onset of the next succeeding ovulation that sexual intercourse can occur without conception occurring since during this period the female ovum has not yet been produced by the woman. However, significant risks do exist with the "rhythm" method since, even if the woman has not ovulated at the time of sexual intercourse, ovulation occurring one or two days thereafter can result in conception since the life span of male sperm in the vagina can be as long as one to two days, and sometimes longer.
Some methods do exist for determining when a woman is about to ovulate but these are inconvenient and difficult to interpret. One such method requires the woman to take her temperature every morning and to plot this on a graph. From the shape of the graph, it is possible to see when ovulation has actually occurred, but the major problems associated with this method is that fluctuations in body temperature can occur for many reasons other than the ovulation process.
It is also well known to this art that a surge in the level of human luteinizing hormone (hLH or HL) takes place about 34 hours prior to ovulation. It takes place according to considerations which can begin by first noting that the normal human menstrual cycle is divided into the follicular phase, ovulation, and the luteal phase. Normal hormonal control during the follicular phase produces maturation of the primary ovarian follicle. Human luteinizing hormone and human follicle stimulating hormone (hFSH or FSH) are known to have a sensitizing effect upon the primary ovarian follicle. These hormones act in concert to stimulate estrogen synthesis. It is also known that estrogen and hFSH achieve their sensitizing effects by inducing expression of gonadotropin receptors in preparation for ovulation. Estrogen in turn acts on the hypothalamus to control pituitary secretion of gonadotropins. Estrogen reaches a peak one to two days prior to ovulation. This peak in turn induces a positive feedback response in the anterior pituitary to hypothalamic gonadotropin releasing hormone. During this peak period, estrogen levels decrease while progesterone levels start to increase and thereby stimulate the release of high levels of hLH. This surge in the hLH level reaches peaks which are usually two to three times the preceding basal concentrations. This hLH surge in turn induces a rupture of the primary ovarian follicle and the resulting release of a mature oocyte. This phenomenon is generally referred to as "ovulation". Thereafter, hLH promotes luteinization and formation of the corpus luteum. This is followed by a decrease in the hLH level to baseline levels within two days in response to the peaking progesterone levels which serve to initiate the luteal phase which lasts about 14 days. In the absence of fertilization of the oocyte, a new follicle begins the selection procedure for maturation in the next menstrual cycle.
The methods for detecting the hLH surge have also improved in recent times. Before the development of immunoassays, analyses of hLH in urine was obtained by bioassay techniques. However, the clinical utility of these methods was limited; they had relatively low sensitivity and frequently required that urine extracts be tested. In the mid 1960's however, the introduction of radioimmunoassay for hLH provided a new tool for quantitating low levels hLH in urine or serum. The later introduction of enzyme immunoassays for hLH offered the further advantage of good sensitivity without the use of radioisotopes. Nonetheless, there still exists a need for improved methods for evaluating fertility in woman so that fertility problems can be alleviated or so that appropriate birth control methods can be selected. Moreover, the diagnosis of infertility problems is still hampered by the fact that prediction of ovulation does not in and of itself give any information as to whether or not the oocyte which is about to be released is one that is fecund.
Thus even though it is well known that the detection of the hLH surge can act as an important tool in the detection of ovulation since the onset of the hLH surge precedes ovulation by about 34 hours; and even though it is also known that peak hLH levels occur several hours later in urine than in serum with the onset of the surge in urine being about 30 hours before ovulation it has not been heretofore appreciated that differences in hLH and/or hFSH levels before and after ovulation could be used in a diagnostic test aimed at determining whether or not the female is releasing fecund oocytes.